Pathogenic cellular role of the p.L104P human cationic trypsinogen variant in chronic pancreatitis

American Journal of Physiology. Gastrointestinal and Liver Physiology
Anita BalázsMiklós Sahin-Tóth

Abstract

Mutations in the PRSS1 gene encoding human cationic trypsinogen are associated with hereditary and sporadic chronic pancreatitis. High-penetrance PRSS1 mutations found in hereditary pancreatitis alter activation and/or degradation of cationic trypsinogen, thereby promoting intrapancreatic trypsinogen activation. In contrast, a number of rare PRSS1 variants identified in subjects with sporadic chronic pancreatitis cause misfolding and endoplasmic reticulum (ER) stress. Mutation p.L104P is unique among natural PRSS1 variants, since it affects the substrate binding site of trypsin. The aim of the present study was to establish the clinical significance of variant p.L104P through functional analysis. We found that p.L104P trypsin exhibited decreased activity on peptide and protein substrates; however, autoactivation was slightly accelerated. Remarkably, binding of the physiological trypsin inhibitor serine protease inhibitor Kazal type 1 (SPINK1) was decreased by 70-fold. In the presence of the trypsinogen-degrading enzyme chymotrypsin C, mutant p.L104P autoactivated to higher trypsin levels than wild-type trypsinogen. This apparent resistance to degradation was due to slower cleavage at Arg(122) rather than Leu(81) Finally, secret...Continue Reading

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Citations

Jun 15, 2018·Current Opinion in Gastroenterology·Frank U WeissMarkus M Lerch
Jun 27, 2017·Current Opinion in Gastroenterology·Miklós Sahin-Tóth
May 26, 2017·Digestive Diseases and Sciences·Eszter Hegyi, Miklós Sahin-Tóth
Feb 23, 2019·Frontiers in Genetics·Zsanett JancsóMiklós Sahin-Tóth
Jul 19, 2016·Current Opinion in Gastroenterology·Anna S GukovskayaIlya Gukovsky
Jul 1, 2016·The Journal of Biological Chemistry·András SzabóMiklós Sahin-Tóth
Dec 2, 2020·Clinics and Research in Hepatology and Gastroenterology·Emmanuelle GirodonThierry Bienvenu
Aug 11, 2021·Pancreatology : Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]·Vanda ToldiAndrás Szabó

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